Differential reinforcement of low rate performance, pharmacokinetics and pharmacokinetic-pharmacodynamic modeling: independent interaction of alprazolam and caffeine.

To investigate the interaction between alprazolam and caffeine, performance on a differential reinforcement of low-rate behavior schedule and the respective pharmacokinetics (PK) were explored in concurrent studies. Alprazolam PK was not altered by caffeine, but alprazolam retarded caffeine absorption indirectly, as inferred by the lack of i.v. drug administration PK interaction, thereby decreasing serum methylxanthine concentrations. Inasmuch as alprazolam was more potent and short-lived than caffeine in decreasing the reinforcement rate (consonant with their respective t(1/2) values, 0.44 and 3.1 hr), the alprazolam/caffeine potency ratio decreased across the session time, which determined the expression of the combined effects. Thus, the decreased methylxanthine level yielded slightly less disruption in performance for the observed combined effect, compared to the expected calculated effect, only near the end of a session. The interaction was PK linked and mainly not distinguishable from independence as indicated by the Poch dose-response curve method and the integration of PK and pharmacodynamics. The sigmoid maximal effect-link pharmacodynamic model indicated that caffeine did not alter the concentration at half of the maximal effect value of alprazolam and suggested that the interaction is not competitive, but independent. Although the nature of the benzodiazepine-methylxanthine interaction has been controversial in other behavioral studies, as is the role of PK in determining behavior, this and our previous study make it evident that the interaction is independent not only across doses and routes of administration, but also with respect to two indices of differential reinforcement of low rate performance.